CN109152750B - 用于增殖性疾病的组合疗法 - Google Patents
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Abstract
一种组合产品,其包含:(A)式(I)R‑L‑CO‑X的化合物或其盐和(B)式(X)的化合物或其互变异构体或其药学上可接受的盐或其水合物或其溶剂化物,其中R为C10‑24不饱和烃基,任选地被一个或多个选自S、O、N、SO、SO2的杂原子或杂原子基团间隔,所述烃基包含至少4个非共轭双键;L为在R基团和羰基CO之间形成1至5个原子的桥的连接基团,其中在连接基团的主链中L包含至少一个杂原子;以及X为吸电子基团;其中R1为苯基,其中所述苯基被未取代的低级烷基或被氰基取代的低级烷基取代;R3为低级烷基,例如甲基;以及R4为未取代的喹啉基或被卤素取代的喹啉基。
Description
技术领域
本发明涉及药物组合物或组合产品,其包含某些多不饱和长链酮与某些蛋白激酶抑制剂、特别是磷脂酰肌醇-4,5-二磷酸3-激酶抑制剂(PI3K)、更特别是PI3K和雷帕霉素(mTOR)的哺乳动物靶标的双重抑制剂的组合。本发明还涉及所述药物组合物或组合产品用于治疗或预防增殖性病症(例如癌症,诸如乳腺癌)的用途。本发明还涉及治疗或预防患者中的增殖性病症的方法,所述方法包括给患者施用本发明的药物组合物或组合产品。
背景技术
基底样乳腺癌(BLBC)占所有乳腺癌的约15%,是与不良预后相关的疾病的侵袭性分子亚型。大多数BLBC是三阴性的(缺乏雌激素受体、孕酮受体和人表皮生长因子受体2的表达),因此对目前可用的靶向疗法无反应。因此,需要新的用于治疗的分子靶点。
本发明人设计了一种新的组合疗法,其一般针对增殖性病症并特别针对乳腺癌。
本发明依赖于长链多不饱和酮化合物与PI3K和mTOR的特异性双重抑制剂的组合。本发明人惊奇地发现,这两种化合物的组合导致协同作用的组合疗法。特别地,已显示该组合协同地降低乳腺癌细胞活力。
发明内容
因此,从一方面来看,本发明提供了一种药物组合物,其包含:
(A)式(I)的化合物,或其盐:
R-L-CO-X (I)
其中R为C10-24不饱和烃基,任选地被一个或多个选自S、O、N、SO、SO2的杂原子或杂原子基团间隔,所述烃基包含至少4个非共轭双键;
L为在R基团和羰基CO之间形成1至5个原子的桥的连接基团,其中在连接基团的主链中L包含至少一个杂原子;以及
X为吸电子基团;和
(B)式(X)的化合物,或其互变异构体,或其药学上可接受的盐,或其水合物或其溶剂化物
其中R1为苯基,其中所述苯基被未取代的低级烷基或被氰基取代的低级烷基取代;
R3为低级烷基,例如甲基;以及
R4为未取代的喹啉基或被卤素取代的喹啉基。
从另一方面来看,本发明提供了一种用于同时、顺序或单独使用的组合产品,其包含:
(A)式(I)的化合物,或其盐:
R-L-CO-X (I)
其中R为C10-24不饱和烃基,任选地被一个或多个选自S、O、N、SO、SO2的杂原子或杂原子基团间隔,所述烃基包含至少4个非共轭双键;
L为在R基团和羰基CO之间形成1至5个原子的桥的连接基团,其中在连接基团的主链中L包含至少一个杂原子;以及
X为吸电子基团;和
(B)式(X)的化合物,或其互变异构体,或其药学上可接受的盐,或其水合物或其溶剂化物
其中R1为苯基,其中所述苯基被未取代的低级烷基或被氰基取代的低级烷基取代;
R3为低级烷基,例如甲基;以及
R4为未取代的喹啉基或被卤素取代的喹啉基。
从另一方面来看,本发明提供了一种用于同时、顺序或单独使用的药物试剂盒组合物,其包含第一组合物和第二组合物,所述第一组合物包含如本文所定义的化合物(I)和药学上可接受的稀释剂或载体,所述第二组合物包含如本文所定义的化合物(X)和药学上可接受的稀释剂或载体。
特别地,本发明涉及一种如上文所定义的药物组合物、组合产品或试剂盒,其中式(I)的化合物为:
或者
或其盐;以及
式(X)的化合物为
或其盐。
从另一方面来看,本发明提供如上文所定义的药物组合物或组合产品用于治疗或预防增殖性疾病,例如癌症,尤其是乳腺癌。
从另一方面来看,本发明提供了一种治疗或预防有需要的患者中的增殖性疾病的方法,所述增殖性疾病例如为癌症,尤其是乳腺癌,该方法包括给所述患者(优选人)施用有效量的如上文所定义的组合物或组合产品。
从另一方面来看,本发明提供了一种治疗(例如减轻增殖性疾病的症状)或预防有需要的患者中的增殖性疾病的方法,所述增殖性疾病例如为癌症,尤其是乳腺癌,该方法包括给所述患者(优选人)施用有效量的式(I)的化合物,同时、分别或顺序给所述患者施用如上文所定义的式(X)的化合物。在顺序施用中,可以首先施用任一种化合物。
从另一方面来看,本发明提供了一种治疗(例如减轻增殖性疾病的症状)或预防有需要的患者中的增殖性疾病的方法,所述增殖性疾病例如为癌症,尤其是乳腺癌,该方法包括:
(i)辨别已经分别接受如上文所定义的式(I)的化合物或式(X)的化合物的患者;
(ii)给所述患者施用有效量的如上文所定义的式(X)的化合物或式(I)的化合物,使得所述患者被施用式(I)的化合物和式(X)的化合物。
从另一方面来看,本发明提供了如上文所定义的组合物或组合产品在制备用于治疗或预防增殖性疾病(例如癌症、特别是乳腺癌)的药物中的用途。
从另一方面来看,本发明提供了一种用于制备如上文所定义的组合物的方法,该方法包括在至少一种药物赋形剂的存在下将式(I)的化合物和式(X)的化合物进行共混。
定义
术语低级烷基在本文中用于指C1-6烷基基团,优选为C1-4烷基基团,尤其是C1-3烷基基团。这些烷基基团可以是直链的或支链的,优选为直链的。
本发明涉及药物组合物和组合产品(例如试剂盒),药物组合物中化合物(I)和(X)在单一组合物中共混在一起,组合产品中活性化合物以单独的组分提供但设计用于同时、分别或顺序施用。本文所定义的任何治疗或预防增殖性疾病的方法包括同时、分别或顺序施用本发明的活性组分或施用本发明的组合物。
根据本发明的“组合”是指一种剂量单位形式的固定组合、或组合施用的部分的试剂盒,其中式(I)的化合物及其组合搭档式(X)的化合物(也被称作“组合搭档”或“治疗剂”)可以同时独立施用或在时间间隔内单独施用,特别是在这些时间间隔允许组合搭档显示出合作且优选协同效应的情况下。
如本文所用的“组合产品”是指适合于药物用途的产品,该产品由多于一种活性成分的混合或组合产生,并且包括活性成分的固定和非固定组合。术语“固定组合”或“固定剂量”是指活性成分、例如式(I)的化合物及其组合搭档式(X)的化合物以单一实体或剂量的形式同时施用给患者。术语“非固定组合”是指活性成分、例如式(I)的化合物和组合搭档式(X)的化合物作为单独的实体同时、并发或顺序地(没有特定的时间限制)施用给患者,其中这样的施用在有需要的温血动物体内提供治疗有效水平的两种化合物。
以下关于本发明的优选化合物的所有讨论同样适用于本发明的这些方面。
具体实施方式
本发明涉及式(I)的化合物和式(X)的化合物的组合疗法。我们惊奇地发现这种组合疗法产生协同作用。我们的研究结果表明,乳腺癌细胞的活力降低,组合物或组合产品的降低幅度大于单独使用单个化合物所预期的降低幅度,即化合物的组合产生的总体效果大于各个要素的总和。
增殖性疾病
本发明涉及一种用于增殖性疾病的新的组合疗法。优选地,本发明的组合物用于治疗选自良性肿瘤或恶性肿瘤,脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳腺癌、胃癌、胃肿瘤、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌或甲状腺癌、肉瘤、胶质母细胞瘤、多发性骨髓瘤或胃肠癌的增殖性疾病。
如果增殖性疾病是乳腺癌,则是特别优选的。本发明的组合物或组合产品可以特异性靶向转移性乳腺癌。
本发明的组合物或组合产品
本发明依赖于式(I)的化合物和式(X)的化合物的治疗组合。式(I)的化合物是
R-L-CO-X (I)
或其盐,
其中R为C10-24不饱和烃基,任选地被一个或多个选自S、O、N、SO、SO2的杂原子或杂原子基团间隔,所述烃基包含至少4个非共轭双键;
L为在R基团和羰基CO之间形成1至5个原子的桥的连接基团,其中在连接基团的主链中L包含至少一个杂原子;以及
X为吸电子基团。
基团R优选包含5至9个双键,优选为5或8个双键,例如5至7个双键,例如5或6个双键。这些键应该是非共轭的。如果双键不与羰基官能团共轭,则也是优选的。
存在于基团R中的双键可以是顺式或反式构型,但是,如果存在的大部分双键(即至少50%)是顺式构型,则是优选的。在进一步有利的实施方案中,基团R中的所有双键均为顺式构型,或者除了最接近羰基的双键可以是反式构型外,所有双键均为顺式构型。
基团R可具有10至24个之间的碳原子,优选12至20个碳原子,特别是17至19个碳原子。
虽然R基团可被至少一个杂原子或杂原子基团间隔,但这不是优选的,R基团主链优选仅含有碳原子。
R基团可带有至多三个取代基,例如选自卤素、C1-6烷基(例如甲基)或C1-6烷氧基。如果存在,取代基优选为非极性的并且小的,例如甲基。然而,如果R基团保持未取代,则是优选的。
R基团优选为亚烷基基团。
R基团优选是直链的。它优选衍生自天然来源,例如长链脂肪酸或酯。特别地,R基团可以衍生自AA、EPA或DHA。
因此,从另一方面来看,本发明使用式(I')的化合物,或其盐
R-L-CO-X (I')
其中R为C10-24未取代的不饱和亚烷基基团,所述基团包含至少4个非共轭双键;
L为在R基团和羰基CO之间形成1至5个原子的桥的连接基团,其中在连接基团的主链中L包含至少一个杂原子;以及
X为吸电子基团。
理想情况下R为直链的。因此,R优选为不饱和C10-24多亚烷基链。
连接基团L在R基团和羰基之间提供1至5个主链原子、优选2至4个主链原子、例如2个原子的桥连基团。接头(linker)主链中的原子可以是碳和/或是杂原子,例如N、O、S、SO、SO2。原子不应形成环的一部分,连接基团的主链原子可以被侧链取代,例如被具有诸如C1-6烷基、氧代、烷氧基或卤素的基团取代。
连接基团的优选组分是-CH2-、-CH(C1-6烷基)-、-N(C1-6烷基)-、-NH-、-S-、-O-、-CH=CH-、-CO-、-SO-、-SO2-,这些基团可以以任何(化学上有意义的)顺序相互组合形成连接基团。因此,通过使用两个亚甲基和-S-基团,形成接头-SCH2CH2-。应理解的是,接头的至少一个组分在主链中提供杂原子。
连接基团L在主链中含有至少一个杂原子。如果与R基团连接的连接基团的第一主链原子是杂原子或杂原子基团,则也是优选的。
如果连接基团L在主链中含有至少一个-CH2-连接单元(link),则是非常优选的。理想地,与羰基相邻的连接基团的原子是-CH2-。
优选的是,基团R或基团L(取决于L基团的大小)提供杂原子或杂原子基团,所述杂原子或杂原子基团位于羰基的α、β、γ或δ位,优选为羰基的β或γ位。优选地,杂原子为O、N或S或硫衍生物如SO。
因此,高度优选的连接基团L为-NH2CH2、-NH(Me)CH2-、-SCH2-、-SOCH2-或-COCH2-。
连接基团应不包含环。
高度优选的连接基团L为SCH2、NHCH2和N(Me)CH2。
从另一方面来看,本发明使用式(II)的化合物,或其盐
R-L-CO-X (II)
其中R为直链未取代的C10-24不饱和亚烷基基团,所述基团包含至少4个非共轭双键;
L为-SCH2-、-OCH2-、-SOCH2或-SO2CH2-;以及
X为吸电子基团。
基团X为吸电子基团。在这方面,合适的基团包括O-C1-6烷基、CN、OCO2-C1-6烷基、苯基、CHal3、CHal2H、CHalH2、其中Hal表示卤素,例如氟、氯、溴或碘,优选为氟。
在优选的实施方案中,吸电子基团为CHal3,尤其是CF3。
因此,优选的式(I)的化合物是式(III)的化合物
R-Y1-Y2-CO-X (III)
其中R和X如上文所定义的;
Y1选自O、S、NH、N(C1-6-烷基)、SO或SO2,以及
Y2为(CH2)n或CH(C1-6烷基);或者
其中n为1至3,优选为1。
更优选的式(I)的化合物是式(IV)的化合物
R-Y1-CH2-CO-X (IV)
其中R为直链未取代的C10-24不饱和亚烷基基团,所述基团包含至少4个非共轭双键;
X如上文所定义的,例如为CF3;和
Y1选自O、S、SO或SO2。
用于本发明的高度优选的化合物如下所述。
其中X如上文所定义的,例如为CF3。
以下用于本发明的化合物是高度优选的:
本发明组合物或产品的第二组分是如上文所定义的式(X)的化合物。在式(X)的化合物中,如果R1是苯基,其中所述苯基被低级烷基取代,低级烷基被氰基取代,则是优选的。
如果R3是甲基,则是优选的。如果R4是未取代的喹啉基,则是优选的。如果喹啉基团R4通过其含N环、特别是通过其3-位键合,则是优选的。
式(X)的化合物优选为式(XI)的化合物,或其盐
其中R1为苯基,其中所述苯基被未取代的低级烷基或被氰基取代的低级烷基取代;
R3为甲基;和
R4为未取代的喹啉基或被卤素取代的喹啉基。
如果化合物(X)是2-甲基-[4-(3-甲基-2-氧代-8-喹啉-3-基-2,3-二氢-咪唑并[4,5-c]喹啉-1-基)-苯基-丙腈或其盐,例如其甲苯磺酸盐,即化合物:
或其盐(例如其甲苯磺酸盐),则是特别优选的。该化合物称为BEZ235。
因此,在最优选的实施方案中,本发明涉及包含化合物A或化合物B和BEZ235的组合物或组合产品。或者,本发明的另一组合产品是BEZ235、化合物A和化合物B。
在可能的情况下,本发明化合物可以以盐、水合物或溶剂化物形式、尤其是盐形式施用。
通常,通过使用所需的酸可以容易地制备药学上可接受的盐。盐可以从溶液中沉淀出来并通过过滤收集,或者可以通过蒸发溶剂来回收。例如,可以将酸(例如盐酸)的水溶液加入到式(X)的化合物的水悬浮液中,将所得混合物蒸发至干(冻干)以得到作为固体的酸加成盐。或者,可以将式(X)的化合物溶解在合适的溶剂(例如醇、诸如异丙醇)中,并且可以将酸加入相同的溶剂或另一种合适的溶剂中。然后可以直接沉淀所得的酸加成盐,或者通过加入极性较小的溶剂(例如二异丙醚或己烷)沉淀,并通过过滤分离。
合适的加成盐由形成无毒盐的无机酸或有机酸形成,示例是盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、磷酸氢盐、乙酸盐、三氟乙酸盐、马来酸盐、苹果酸盐、富马酸盐、乳酸盐、酒石酸盐、柠檬酸盐、甲酸盐、葡糖酸盐、琥珀酸盐、丙酮酸盐、草酸盐、草酰乙酸盐、三氟乙酸盐、糖酸盐、苯甲酸盐、烷基或芳基磺酸盐(例如甲磺酸盐、乙磺酸盐、苯磺酸盐或对甲苯磺酸盐)和羟乙基磺酸盐。代表性示例包括三氟乙酸盐和甲酸盐,例如双(三氟乙酸盐)或三(三氟乙酸盐)和单甲酸盐或二甲酸盐,特别是三(三氟乙酸盐)或双(三氟乙酸盐)和单甲酸盐。
式(I)的化合物可使用已知的化学合成途径制备。从可商购获得的化合物花生四烯酸(AA)、EPA(全-Z-二十碳-5,8,11,14,17-五烯酸)或DHA(全-Z-二十二碳-4,7,10,13,16,19-六烯酸)开始合成是方便的。可以容易实现将这些化合物的酸官能团转化为例如-COCF3基团,例如通过将羧酸转化为其相应的酰氯并在吡啶的存在下使酰氯与三氟乙酸酐反应。
也容易实现将杂原子引入碳链。方便地,例如,将起始酸还原为醇,并且如果需要,转化为相应的硫醇。然后亲核硫醇可以与例如BrCH2COCF3的基团反应,从而引入羰基和吸电子物质。完整的合成方案可以参见Chem.Soc.,Perkin Trans 1,2000,2271-2276或者J.Immunol.,1998,161,3421。
用于制备式(X)的化合物的合成方法描述于例如EP-A-1888578中。已经描述了用于测定PI3K抑制剂、mTOR抑制剂和双PI3K/mTOR抑制剂的活性的其它方法。例如参见WO2015/04939和美国专利出版物2014/0066474、以及Brana等人(2012)BMC Med.10:161。本发明组合物或组合产品中式(I)的化合物与式(X)的化合物的重量比将由预期用途、受试者的年龄和一般健康状况以及本领域技术人员已知的其它参数指导。例如,适合于某些应用的特定重量比可以是10比90重量%至90比10重量%,例如30比70重量%至70比30重量%。
更优选地,每种化合物的量以摩尔的术语确定,并且各自的比例为5:1至1:5摩尔,例如2:1至1:2摩尔。通常,化合物以等摩尔量用于某些应用。
组合物中本发明的化合物的量通常由医师根据所需剂量确定。
提出本发明的组合物或组合产品主要用于治疗或预防增殖性疾病(例如癌症)。
治疗(treating)或治疗(treatment)是指至少下列之一:
(i)抑制疾病,即阻止、减少或延迟疾病的发展或其复发或其至少一种临床或亚临床症状,或者
(ii)缓解或减轻疾病的一种或多种临床或亚临床症状。
预防是指(i)预防或延迟哺乳动物中发生的疾病的临床症状的出现。
对于待治疗的受试者的益处是统计学上显著的或至少对患者或医师是可察觉的。通常,技术人员可以理解何时发生“治疗”。如果本发明的组合物或组合产品在治疗上使用,即治疗已表现出来而非预防的病症,则是特别优选的。可能的是,本发明的组合物或组合产品在治疗上使用比预防性使用时更有效。
本发明的组合物或组合产品可用于任何动物受试者,特别是哺乳动物,更特别地用于人或作为疾病模型的动物(例如小鼠、猴子等)。
为了治疗疾病,需要将有效量的活性组合物或组合产品施用给患者。“治疗有效量”是指当施用给动物用于治疗病情、疾病或病症时,足以实现这种治疗的组合物或组合产品的量。“治疗有效量”将根据组合物或组合产品、疾病及其严重程度以及待治疗受试者的年龄、体重、身体状况和反应性而变化,并且最终由主治医生决定。
为了根据本发明治疗癌症,必须以一定的间隔重复施用本发明的组合物或组合产品。合适的剂量方案可由医师开处方。
本发明的组合物或组合产品通常包含活性组分与至少一种药学上可接受的载体的混合物,所述载体是根据预期的给药途径和标准药学实践选择的。
术语“载体”是指与活性化合物一起施用的稀释剂、赋形剂和/或载剂(vehicle)。本发明的药物组合物可含有多于一种的载体的组合。这种药物载体在本领域中是众所周知的。药物组合物还可包含任何合适的粘合剂、润滑剂、悬浮剂、包衣剂和/或增溶剂等。该组合物还可含有其它活性成分,例如用于治疗癌症的其它药物。
应当理解,根据本发明使用的药物组合物或组合产品可以是口服、肠胃外、透皮、舌下、局部、植入、鼻腔或肠内施用(或其它粘膜施用)悬浮液、胶囊或片剂的形式,其可以使用一种或多种药学上可接受的载体或赋形剂以常规方式配制。本发明的组合物也可以配制成纳米颗粒制剂。
然而,对于癌症的治疗,本发明的组合物或组合产品优选口服施用或通过肠胃外或静脉内施用,例如注射施用。因此,组合物或组合产品可以以片剂或注射用溶液的形式提供。
本发明的药物组合物或组合产品可含有0.01至99%重量-每体积的活性物质。治疗剂量通常在约10至2000毫克/天之间,优选在约30至1500毫克/天之间。可以使用其它范围,包括例如50至500毫克/天,50至300毫克/天,100至200毫克/天。
施用可以是每天一次、每天两次、或更经常,并且可以在疾病或病症的维持期的期间减少,例如,每隔一天一次或每隔两天一次,而不是每天一次或每天两次。剂量和施用频率将取决于临床体征,临床体征确认缓解期的维持,缓解期具有本领域技术人员已知的至少一种或多种(优选超过一种)急性期临床体征的减少或缺失。
将本文所述的组合产品施用给已暴露于、正暴露于或将暴露于一种或多种抗增殖化合物(特别是已知用于许多抗癌疗法的那些)的受试者,是在本发明的范围内。非限制性示例包括芳香酶抑制剂、抗雌激素药、拓扑异构酶I或II抑制剂、微管活性化合物、烷基化化合物、组蛋白去乙酰化酶抑制剂和环加氧酶抑制剂,例如WO2006/122806和其中引用的参考文献中公开的那些。是否将本发明的组合产品与一种或多种上述抗癌疗法组合的选择将由本领域技术人员已知的公认参数指导,包括所治疗的癌症的特定类型、受试者的年龄和健康等。
下面参考以下非限制性示例和附图进一步描述本发明。
附图说明
图1示出了用cPLA2α抑制剂化合物B和BEZ235的共处理,与单独的每种抑制剂相比,显示出对乳腺癌细胞活力的协同作用。在8个孔中进行的4次实验的平均值和标准偏差。
示例:
实验中使用以下化合物:
方法
细胞培养。MDA-MB-468细胞系来自ATCC。该细胞系由患有转移性乳腺癌的患者的胸腔积液建立。在37℃下,5%CO2中,将细胞维持在补充有10%(体积/体积)FBS、0.3mg/mLL-谷氨酰胺和0.1mg/mL庆大霉素的RPMI培养基中。每3至4天进行使用胰蛋白酶-EDTA进行传代培养,分流比为1:3至1:6,以确保活跃的增殖细胞。
刃天青活力测定。将细胞以每孔7000个细胞的密度接种在96孔板中的完全补充的培养基中。培养24小时后,当细胞约60%汇合时,用无血清培养基替换培养基以确保细胞的同步性并增加细胞对处理的敏感性。在血清饥饿16小时后,用含有或不含化合物B(Avexxin,Norway)和NVP-BEZ235(Cayman Chemicals,US)或溶剂(DMSO,Sigma Aldrich,US)的新鲜无血清培养基替换培养基。在显微镜下观察细胞以在根据制造商的说明书(RnDSystems,UK)加入刃天青之前评估可能的形态变化和应激迹象。将刃天青代谢2小时(37℃,5%CO2),然后在544nm激发和590nm发射波长(BioTek Synergy HT)下读取荧光。
结果
与单独的每种抑制剂相比,用cPLA2α抑制剂化合物B和PI3K/mTOR抑制剂NVP-BEZ235共处理显示出对乳腺癌细胞活力的协同作用。进行初始实验以确定单独的每种抑制剂的作用。化合物B和BEZ235在25至100μM对细胞有毒,而在1至5μM的剂量下,观察到很少或没有观察到细胞毒性的细胞应激的迹象(结果未示出)。在此基础上,设计了组合处理实验,其中组合了亚毒性剂量的抑制剂。处理24小时后,5μM的BEZ235和化合物B分别中度降低活力约30%和20%。然而,当组合5μM的两种抑制剂时,发现活力降低70%,表明对癌细胞增殖具有协同和有益作用(图1)。在统计学上,我们的结果显示:¤p<0.005vs对照且#p<0.0005vs单一处理。
Claims (11)
3.根据权利要求1或2所述的用于治疗或预防增殖性疾病的组合产品或药物组合物,其中式(X)的化合物的药学上可接受的盐为它的4-甲苯磺酸盐。
4.根据权利要求1或2所述的用于治疗或预防增殖性疾病的组合产品或药物组合物,其中所述组合产品或药物组合物是固定组合或非固定组合。
6.根据权利要求5所述的用于治疗或预防增殖性疾病的同时、顺序或单独使用的药物组合物,其中所述药物组合物是固定组合或非固定组合。
7.根据权利要求1至6中任一项所述的药物组合物或组合产品在制备用于治疗或预防增殖性疾病的药物中的用途。
8.根据权利要求7所述的用途,其中所述增殖性疾病为癌症。
9.根据权利要求8所述的用途,其中所述增殖性疾病为乳腺癌。
10.根据权利要求7至9中任一项所述的用途,包括给患者施用有效量的化合物A或B,并同时、分别或顺序给所述患者施用式(X)的化合物。
11.根据权利要求7至9中任一项所述的用途,其中所述用途包括:
(i)辨别已经接受化合物A或B的患者或已经接受式(X)的化合物的患者;
(ii)给已经接受化合物A或B的患者施用有效量的式(X)的化合物或给已经接受式(X)的化合物的患者施用有效量的化合物A或B,使得所述患者被施用化合物A或B和式(X)的化合物两者。
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CA3017557A1 (en) | 2017-09-21 |
US10953004B2 (en) | 2021-03-23 |
AU2017235350A1 (en) | 2018-11-01 |
JP7027324B2 (ja) | 2022-03-01 |
WO2017157955A1 (en) | 2017-09-21 |
ES2877809T3 (es) | 2021-11-17 |
EP3429572B1 (en) | 2021-05-05 |
US20190076423A1 (en) | 2019-03-14 |
CN109152750A (zh) | 2019-01-04 |
EP3429572A1 (en) | 2019-01-23 |
AU2017235350B2 (en) | 2020-04-02 |
JP2019508457A (ja) | 2019-03-28 |
GB201604316D0 (en) | 2016-04-27 |
KR102410362B1 (ko) | 2022-06-16 |
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